Environmental agonists of the Aryl Hydrocarbon Receptor (AHR) such as TCDD (dioxin) and polycyclic aromatic hydrocarbons generate a chronic inflammatory and immunosuppressive tissue microenvironment that can promote cancer development. While a direct role of the AHR in cancer pathogenesis has not been demonstrated, recent studies show that increased levels of nuclear AHR correlate with tumor grade in urothelial carcinoma and breast cancer, and that many genes involved in the malignant phenotype of tumor cells are directly regulated by the AHR. More recently, it has become evident that the AHR plays a role in normal physiology and disease pathology through the action of endogenous agonists. The AHR is also critical for differentiation of proinflammatory Th17 cells and plays an important role in function these and of innate immune cells such as dendritic cells and macrophages in responses to infection, autoimmunity and inflammatory diseases. These physiological functions are likely to be mediated by recently identified endogenous AHR ligands. While AHR modulated proinflammatory signaling has been described in tumor cells, and critical relevance of the AHR in normal and pathological immune function has been documented, there is no information on the contribution of tumor cell or immune cell AHR to cancer driven inflammation. Newly developed AHR ligands that can prevent DRE and non-DRE AHR activities have the potential to suppress inflammatory signaling either in response to environmental or endogenous agonists, and thus be important drugs for the prevention and therapy of cancer, but more detailed information on the mechanism of action and critical target cells is required. The overall goal of this exploratory grant proposal is to determine the relative contribution to cancer inflammation and tumor development of the AHR in epithelial and immune cell compartments, and to determine if AHR selective modulators suppress inflammation through actions on tumor cell or immune cell AHR. If successful these initial studies will provide the first demonstration for a role leukocyte AHR in cancer inflammation and the impetus for more detailed structure/function analysis of AHR antagonists in other cancer models that could provide important new information for use of these compounds as anti-cancer therapeutics. PUBLIC HEALTH RELEVANCE: Environmental agonists of the Aryl Hydrocarbon Receptor (AHR) such as TCDD (dioxin) and polycyclic aromatic hydrocarbons generate both chronic inflammatory and immunosuppressive responses through activation of proinflammatory gene expression that can lead to a cancer promoting tissue microenvironment. The AHR also plays a role in normal physiological process through the action of recently identified endogenous ligands, and increased levels and nuclear localization of the AHR has been linked to more aggressive cancer grade. This proposal will examine whether AHR in immune cells or tumor cells is critical for generation of cancer inflammation and whether small molecule modulators of the AHR have potential as anti-cancer therapeutics through a blockade of cancer promoting proinflammatory gene expression.